News From The Journal Of Clinical Investigation: Nov. 19, 2012

Bone marrow transplant (BMT) patients and the elderly suffer from a loss of thymic function, resulting in low T cell production and greater susceptibility to infection. Several previous studies have indicated that T cells can develop outside the thymus; however, it is unclear if these cells are fully functional. In this issue of the Journal of Clinical Investigation, researchers led by Marcel van den Brink at Memorial Sloan-Kettering Hospital used a mouse model of BMT to determine if extrathymic T cell development could produce functional T cells. Van den Brink and colleagues found that mice with impaired thymic function after BMT produced fully functional T cells, demonstrating that lymph nodes can support T cell development in the absence of thymic function. These results suggest that patients with limited thymic function can still produce functional T cells and that these pathways could be therapeutically targeted to enhance functional T cell populations.

Myotopic Dystrophy type 1 (DM1), also known as Steinert disease, is a congenital neuromuscular disease characterized by wasting of the muscle, muscle weakness, endocrine changes, and cognitive problems. It is caused by the insertion of nucleotide repeats in the DMPK gene. In this issue of the Journal of Clinical Investigation, researchers led by Lubov Timchenko at Baylor College of Medicine used a mouse model of DM1 to identify dysregulated signaling pathways that contribute to disease progression. Timchenko and colleagues found that GSK3β signaling was increased in DM1 mice and that inhibition of GSK3β reduced muscle weakness and wasting. These results suggest that therapies that normalize GSK3β activity may help improve muscle function in DM1 patients.

HIV-1 disables the immune system, leaving patients susceptible to viral and bacterial infections. Dendritic cells (DCs) are a population of immune cells that are involved in controlling HIV infection, leading Nina Bhardwaj and researchers at New York University to hypothesize that factors elicited by HIV-1 might block the function of DCs. In this issue of the Journal of Clinical Investigation, Bhardwaj and colleagues report that microparticles found in the plasma of HIV-1 patients inhibited the function of normal DCs and induced dendritic cell death. These results suggest that inhibition of these microparticles could promote DC activity and survival and help fight HIV-1.

In multiple sclerosis (MS), the blood-brain barrier (BBB) is compromised, allowing immune cells to attack the central nervous system (CNS). B cells are a population of immune cells that are thought to trigger autoimmune responses in MS, but it is unclear if they are able to transverse the BBB. In this issue of the Journal of Clinical Investigation, researchers led by Hans-Christian von Büdingen at the University of California, San Francisco, studied the ability of B cells to move between the peripheral blood and the CNS. By comparing the antibodies in the cerebrospinal fluid and the blood stream, von Büdingen and colleagues found populations of B cells that are common to both areas in patients with MS. This study demonstrates that B cells can cross the BBB and shows that they are central regulators of the pathological immune response in MS.

Chikungunya virus (CHIKV) is a mosquito-borne virus that causes fever and severe joint pain. It is occurring with increasing frequency in Africa, Asia, and the Indian sub-continent, but there are not any treatments for the disease. The human immune system can eventually repel the virus; however, the immune response mechanisms are undefined. In a study published in the Journal of Clinical Investigation, researchers led by Lisa Ng at the Singapore Immunology Network examined the immune cells of human Chikungunya patients. They found that the expression of the protein viperin increased significantly in monocytes, the cells that are primarily targeted by CHIKV. Viperin attenuated viral replication and mice lacking viperin had a greater viral load and more severe joint inflammation compared to normal mice. These data demonstrate that virperin is a critical host protein that controls CHIKV infections and suggest that therapeutics that modulate viperin may be useful in treating similar viruses.

Atherothrombosis, or the formation of a clot in an artery, is one of the major causes of heart attack, stroke, and peripheral artery disease. Clot formation is primarily regulated by the endothelium, the cells which line the insides of the arteries and veins. Previously, researchers led by Mukesh Jain at Case Western Reserve University identified KLF4 as a protective factor that was induced by blood flow and was associated with reduced clot formation. In this issue of the Journal of Clinical Investigation, Jain and colleagues examined atherosclerotic plaque formation in KLF4 mutant mice fed a high fat diet. They found that mice lacking KLF4 had significantly enhanced atherosclerosis compared to normal mice, while mice with extra KLF4 had reduced atherosclerosis. These results establish KLF4 as a key regulator of atherothrombosis.

The protein SH2B1 interacts with cell surface receptors that mediate signaling by insulin and leptin, two hormones that are associated with obesity. Mice lacking Sh2b1 exhibit increased food intake, obesity, and insulin resistance. In a study published in the Journal of Clinical Investigation, researchers led by Sadaf Farooqi at Addenbrooke's Hospital in Cambridge, England identified a mutation in SH2B1 in a group of patients with severe early onset diabetes. These patients had increased food intake, early childhood obesity, insulin resistance, and short stature. This study demonstrates that SH2B1 plays a critical role in human food intake and obesity.

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